Total Synthesis of (+)-Aloperine. Use of a Nitrogen-Bound Silicon Tether in an Intramolecular Diels−Alder Reaction

Enantioselective total syntheses of aloperine ( 1 ), N -methylaloperine ( 2 ), and N -allylaloperine ( 3 ) are reported. The central element of the synthetic strategy is an intramolecular Diels−Alder reaction in which the cycloaddends are tethered by a N -silylamine linkage. The total synthesis of 1 proceeds from commercially available 3-hydroxypiperidine hydrochloride ( 54 ) and ( R )-pipecolinic acid ( 35 ) by way of nine isolated and purified intermediates. The synthesis is sufficiently efficient that gram quantities of (+)-aloperine ( 1 ) can be readily prepared. Early exploratory studies also introduced a convenient method for tethering cycloaddition partners with a sulfonamide unit to realize the intramolecular Diels−Alder cycloaddition of a vinylsulfonamide: 45 → 46 .